The effects of different doses of exercise on pancreatic β-cell function in patients with newly diagnosed type 2 diabetes: study protocol for and rationale behind the "DOSE-EX" multi-arm parallel-group randomised clinical trial

Mark P P Lyngbaek, Grit E Legaard, Sebastian L Bennetsen, Camilla S Feineis, Villads Rasmussen, Nana Moegelberg, Cecilie F Brinkløv, Anette B Nielsen, Katja S Kofoed, Carsten A Lauridsen, Caroline Ewertsen, Henrik E Poulsen, Robin Christensen, Gerrit Van Hall, Kristian Karstoft, Thomas P J Solomon, Helga Ellingsgaard, Thomas P Almdal, Bente K Pedersen, Mathias Ried-Larsen, Mark P P Lyngbaek, Grit E Legaard, Sebastian L Bennetsen, Camilla S Feineis, Villads Rasmussen, Nana Moegelberg, Cecilie F Brinkløv, Anette B Nielsen, Katja S Kofoed, Carsten A Lauridsen, Caroline Ewertsen, Henrik E Poulsen, Robin Christensen, Gerrit Van Hall, Kristian Karstoft, Thomas P J Solomon, Helga Ellingsgaard, Thomas P Almdal, Bente K Pedersen, Mathias Ried-Larsen

Abstract

Background: Lifestyle intervention, i.e. diet and physical activity, forms the basis for care of type 2 diabetes (T2D). The current physical activity recommendation for T2D is aerobic training for 150 min/week of moderate to vigorous intensity, supplemented with resistance training 2-3 days/week, with no more than two consecutive days without physical activity. The rationale for the recommendations is based on studies showing a reduction in glycated haemoglobin (HbA1c). This reduction is supposed to be caused by increased insulin sensitivity in muscle and adipose tissue, whereas knowledge about effects on abnormalities in the liver and pancreas are scarce, with the majority of evidence stemming from in vitro and animal studies. The aim of this study is to investigate the role of the volume of exercise training as an adjunct to dietary therapy in order to improve the pancreatic β-cell function in T2D patients less than 7 years from diagnosis. The objective of this protocol for the DOSE-EX trial is to describe the scientific rationale in detail and to provide explicit information about study procedures and planned analyses.

Methods/design: In a parallel-group, 4-arm assessor-blinded randomised clinical trial, 80 patients with T2D will be randomly allocated (1:1:1:1, stratified by sex) to 16 weeks in either of the following groups: (1) no intervention (CON), (2) dietary intervention (DCON), (3) dietary intervention and supervised moderate volume exercise (MED), or (4) dietary intervention and supervised high volume exercise (HED). Enrolment was initiated December 15th, 2018, and will continue until N = 80 or December 1st, 2021. Primary outcome is pancreatic beta-cell function assessed as change in late-phase disposition index (DI) from baseline to follow-up assessed by hyperglycaemic clamp. Secondary outcomes include measures of cardiometabolic risk factors and the effect on subsequent complications related to T2D. The study was approved by The Scientific Ethical Committee at the Capital Region of Denmark (H-18038298).

Trial registration: The Effects of Different Doses of Exercise on Pancreatic β-cell Function in Patients With Newly Diagnosed Type 2 Diabetes (DOSE-EX), NCT03769883, registered 10 December 2018 https://ichgcp.net/clinical-trials-registry/NCT03769883 ). Any modification to the protocol, study design, and changes in written participant information will be approved by The Scientific Ethical Committee at the Capital Region of Denmark before effectuation.

Discussion: The data from this study will add knowledge to which volume of exercise training in combination with a dietary intervention is needed to improve β-cell function in T2D. Secondarily, our results will elucidate mechanisms of physical activity mitigating the development of micro- and macrovascular complications correlated with T2D.

Keywords: Exercise; Inflammation; Insulin resistance; Lifestyle intervention; Oxidative stress; Randomised clinical trial; Randomised controlled trial; Type 2 diabetes mellitus; β-cell function.

Conflict of interest statement

The authors declare that they have no competing interests.

Figures

Fig. 1
Fig. 1
Flow of participants through the DOSE-EX study. HED, high exercise dose; MED, moderate exercise dose; DCON, dietary intervention; CON, control group. Steps 1, 2, and 3 refer to the recruitment procedure. Step 1 being the initial contact with possible participants, screening by phone and obtaining informed consent if inclusion criteria are met. In step 2, eligibility is assessed based on blood and urine samples and finally step 3 constitutes a medical examination (see text for details). If no exclusion criteria are identified the participant proceeds to baseline testing and randomisation. Participants are randomly allocated to HED, MED, DCON, or CON in a ratio of 1:1:1:1 stratified by sex
Fig. 2
Fig. 2
Overview of interventions. HED, high exercise dose; MED, moderate exercise dose; DCON, dietary intervention; CON, control group. The intervention runs over a full 16 weeks period. During the 16 weeks, adherence and individual adjustment in the different parts of the intervention (exercise, diet, and pharmacological management) will be evaluated by relevant study personnel. Dietary consulting is provided by the dietician. The coordinating exercise trainer handles consults regarding the exercise intervention and pharmacological management is provided by the study nurse in close collaboration with the blinded endocrinologist. Prior to the dietary consults, each participant will be asked to complete a 3-day dietary record to frame the conversation. Pharmacological adjustments will be based on resent results from blood samples and blood pressure measured at home
Fig. 3
Fig. 3
Overview of weekly exercise sessions. HED, high exercise dose; MED, moderate exercise dose; DCON, dietary intervention; CON, control group
Fig. 4
Fig. 4
Progression in intensity of aerobic training during the intervention. During the 16 weeks, time spend in intensity zone 80–100% of maximum heart rate (HRmax) increases gradually as time spend in intensity zone 60–79% of HRmax decreases. Total aerobic training volume for high exercise dose and moderate exercise dose are 300 and 150 min per intervention week, respectively. Volume remains unchanged throughout the intervention period
Fig. 5
Fig. 5
Resistance training periodisation. Fam, familiarisation period; RIR, repetitions in reserve. The initial 2 weeks of the intervention constitutes a familiarisation period with thorough instruction to each exercise and reduced intensity. The remaining intervention period is divided into blocks ensuring progression towards less repetitions with higher loads. The resistance training frequency for high exercise dose (HED) and moderate exercise dose (MED) are two and one time per week, respectively. RIR tests will be performed four times during the intervention to ensure that participants train with the prescribed intensity
Fig. 6
Fig. 6
Three-stage hyperglycaemic clamp. *Glucose infusion aiming at blood glucose = 5.4 mmol/l above basal. T = time. The hyperglycaemic clamp is used to evaluate beta-cell function. Participants will meet fasting in the laboratory in the morning. After placement of an antecubital venous catheter in both arms, a tracer prime dose (concentration calculated from fasting glucose and body weight) will be injected and infusion of tracers will commence at T = − 120 min. Tracer infusion will continue for 2 h to reach saturation in the circulation. During the 2-h tracer loading period, the muscle and adipose tissue biopsies will be collected. At baseline (time 0), the glucose infusion will be initiated aiming to reach blood glucose concentration at 5.4 mM above fasting. Simultaneously, the tracer infusion rate will be adjusted accordingly. Blood glucose will be measured every 5th minute throughout the remaining clamp and glucose infusion rate (GIR) will be adjusted according to the algorithm. At T = 120 min, the GLP-1 infusion is added. After another hour (T = 180), the arginine bolus is administered, and blood samples are taken continuously for 10 min before ending the clamp

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